The human neocortex is comprised of many areas that perform high-level functions, ranging from basic sensory processes to cognitive thought. Neocortical areas are physiologically and structurally distinct, and are complexly and precisely interconnected. The organization of the neocortex and its connections forms a sophisticated system that generates human thought, perception, action, emotion and cognition. Abnormalities in this system are the basis for many human developmental psychiatric disorders and syndromes. Most alterations occur developmentally, specifically during the time in which the neocortex is divided into discreet, functional areas. The precise mechanisms that control neocortical regionalization represent a topic of great debate. Two major theories have arisen in the last two decades that have suggested potential mechanisms involved in the development of distinct areas in the neocortex. One theory states that processes inherent to the developing neocortical tissue itself, such as gene expression, guide the segregation of the tissue into areas;the other states that neocortical input, especially sensory input, assigns territories and guides regionalization. Since evidence has been presented for both theoretical viewpoints, the current consensus is that both mechanisms are involved in regionalization of the cortex, although their interaction is poorly understood. My experiments directly examine the interactions of the two systems by making large-scale changes in sensory input and examining the resulting changes in neocortical gene expression and connections, at specific developmental time points. For specific aim 1, I plan to first generate a clear map of gene expression in the mouse neocortex from the embryonic period until adulthood, detailing the dynamic changes in timing and position of gene expression. This map will be correlated with areal boundaries determined by analysis of connection patterns and architecture. For specific aim 2, I plan to conduct sensory deprivation experiments in 2 sensory systems at multiple developmental time points. I will analyze how both qualitative and quantitative changes in input levels effect the expression of genes in the neocortex, and how these changes in expression relate to shifts in connections and areal boundaries. The proposed research will directly examine the influence of input, gene expression and their interactions on neocortical regionalization, and how these interactional influences vary by developmental maturity.Many Pervasive Developmental Disorders in children are caused by abnormal brain development that occurs during the time when higher-level brain centers, such as those within the neocortex, are developing. My study directly investigates genetic and experiential influences on the development of the neocortex. By better understanding the mechanisms involved in brain development, we can begin to unravel some of the mysteries of developmental disorders in children.